Primary ductal cells from human pancreas respond to type 1 diabetes inflammatory cytokines in upregulating HLA class II molecules and induce activation and proliferation of autoreactive CD4+ T Cells 4653

Abstract Description A lack of definitive cure for type 1 diabetes (T1D), an autoimmune disease against pancreatic insulin-secreting beta cells, prompts us to examine disease mechanisms involving non-beta cells. Past studies have demonstrated that pancreatic ductal cells in T1D patients have increased HLA class II expression, suggesting a role of ductal cells in non-canonical antigen presentation. We therefore tested whether ductal cells are functionally capable of presenting islet autoantigens to CD4+ T cells. Primary ductal cells from cadaveric donors without apparent diseases were exposed to T1D proinflammatory cytokines (IL1β, TNFα, and IFNγ) in vitro, which caused an upregulation of HLA class II molecules without affecting cell survival. Next, cytokine treated (cyto-) ductal cells were pulsed with GAD65 autoantigen and incubated with an HLA-matched, GAD65-specific CD4+ T cell clone from a T1D patient; after coculture, the CD4+ T cells underwent activation and proliferation. Surprisingly, an activation of CD4+ T cells was also observed when cyto-ductal cells were pulsed with an irrelevant peptide. Immunofluorescence staining demonstrated GAD protein expression in a subpopulation of ductal cells in normal donors. Bulk RNA-seq analysis confirmed upregulation of molecules involved in antigen processing and presentation in cyto-ductal cells. Our results suggest that ductal cells can present autoantigen and activate autoreactive CD4+ T cells, implicating a role of ductal cells in T1D pathogenesis. Funding Sources City of Hope Wanek Family Project for Type 1 Diabetes Topic Categories Immune Mechanisms of Human Disease (HUM)